FGFR fusion

They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms...For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.

P1, N=117, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Mar 2025

P2, N=20, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P1, N=112, Recruiting, Janssen Research & Development, LLC | Trial completion date: Mar 2028 --> Jun 2029

This study underscores the critical role of gene fusions as biomarkers in cancer, extending beyond fusion-driven malignancies to encompass all cancer types. Gene fusions serve as both diagnostic markers and tumor-agnostic therapeutic targets within the current cancer treatment paradigm. Our insights into the prevalence of oncogenic drivers and novel targets expand the understanding of gene fusions, shedding new light on their mechanisms and clinical implications.

P2, N=20, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2028 --> Jun 2029 | Trial primary completion date: Jun 2027 --> Jun 2028

Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.

FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy.

Custom FGFR synthetic reference standards representing both single nucleotide variants (SNVs) and gene rearrangements were utilized at a range of variant frequencies and revealed a detection limit of 0.5% with sensitivities of 97.2% and 92.9% for SNVs and rearrangements, respectively. Furthermore, FGFR-Dx detected rearrangements and identified the intronic breakpoints from cfDNA collected from 13 of 15 patients with known FGFR fusions.

P2, N=107, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Mar 2024 --> Jul 2024

Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.

P2, N=316, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Aug 2022 --> Dec 2023

P1/2, N=47, Terminated, Basilea Pharmaceutica | Phase classification: P1b/2 --> P1/2

P1, N=112, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2027 --> Mar 2028 | Trial primary completion date: Apr 2025 --> Mar 2028

P1/2, N=407, Completed, Taiho Oncology, Inc. | Active, not recruiting --> Completed

P2, N=108, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jul 2025 --> Mar 2025

P2, N=35, Recruiting, National Cancer Institute (NCI) | Initiation date: Jul 2024 --> Jan 2024

P2, N=316, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Sep 2024 --> Oct 2023

However, some patients remained on treatment for up to a year, suggesting that they observed a benefit from treatment. Patients with CCA should undergo molecular testing to identify those who could benefit from targeted treatments such as pemigatinib.

The mainstay of therapy for advanced CCA remains cisplatin plus gemcitabine, with a median overall survival (mOS) under 12 months, although the TOPAZ-1 trial showed a survival benefit with the addition of programmed cell death ligand 1 (PD-L1) blockade. While the role of adjuvant therapy has yet to be defined in this disease, we emphasize the importance of employing targeted therapies in trials in the adjuvant and neoadjuvant spaces and discuss ways to overcome challenges due to low incidence of targetable mutations. Personalized medicine for this disease promises significant clinical benefit to patients, but further investigation is needed.

P2, N=83, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=164 --> 83 | Trial completion date: Jan 2026 --> Nov 2024 | Trial primary completion date: Jan 2026 --> Nov 2024

P2, N=20, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2027

A detailed understanding of the regulation of TACC3 expression, its key partners, and molecular functions in cancer cells is vital for uncovering the most vulnerable tumors and maximizing the therapeutic potential of targeting this highly oncogenic protein. In this review, we summarize the established and emerging interactors and spatiotemporal functions of TACC3 in cancer cells, discuss the potential of TACC3 as a biomarker in cancer, and therapeutic potential of its inhibition.

Whole-transcriptome sequencing allowed the identification of actionable fusions with the potential to affect clinical decisions regarding therapy in 2.8% of RCC patient tumors. In addition, one patient was found to have a fusion that is characteristic of a solitary fibrous tumor, demonstrating the power of genomic profiling to aid diagnosis.

Background: In view of the efficacy of FGFR targeting in early and advanced bladder cancer, as has been shown for erdafitinib in the THOR and NORSE trial, molecular testing of FGFR mutations and fusions will soon become clinical routine worldwide... PCR-based FGFR assessment by Therascreen and UroTyper is highly concordant and enables fast, local FGFR assessment within few hours. FGFR3 mutations are associated with increased TROP2 & NECTIN4 expression indicating potential synergistic options which warrants further exploration as part of molecularly stratified clinical trials.

P1, N=156, Active, not recruiting, AstraZeneca | Phase classification: P1b --> P1 | Trial completion date: Sep 2023 --> Jun 2024

Tasurgratinib (E7090) is an orally available selective inhibitor of FGFR 1–3; the recommended dose is 140 mg per day per the dose-escalation part of a first-in-human phase 1 study...FGFR2 gene fusion was confirmed by fluorescence in situ hybridization performed in central laboratories; ≥ 1 prior chemotherapy regimen including a gemcitabine-based combination was required; pts treated with FGFR2 inhibitors were excluded... Tasurgratinib had promising antitumor activity in pts with CCA harboring FGFR2 gene fusion and who received ≥ 1 prior chemotherapy regimen. The primary endpoint (ORR) met the study’s predefined success criteria. Tasurgratinib had a manageable safety profile consistent with previous reports and with the known pharmacological profile of FGFR inhibitors.

FGFR kinase inhibitorshave the potential to be an effective targeted therapy in pancreas cancer. Additionally, telemedicine is a novel tool that can aid in the study of ultra-rare cancers and reduce barriers to patient participation in clinical trials.

Tinengotinib has promising clinical benefit for FGFR2 fusion CCA after prior FGFRi and for non-fusion FGFR alterations. Tinengotinib-related toxicities were manageable. An ongoing randomized, controlled phase III study will evaluate the clinical efficacy, safety, and pharmacodynamic effect of Tinengotinib vs Physicians’ choice in subjects with FGFR2-altered refractory/relapsed CCA after prior chemotherapy and FGFRi therapy.

P1, N=6, Recruiting, Janssen Pharmaceutical K.K. | Trial completion date: Oct 2026 --> Jul 2027

P2, N=107, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Oct 2024 --> Jul 2025

Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

In addition, for patients who do respond to treatment, secondary resistance frequently develops and mechanisms of such resistance are not fully understood. This review will summarise the current state of development of FGFR inhibitors in CCA, their mechanism of action, activity, and the hypothesised mechanisms of resistance.

P2, N=0, Withdrawn, National Cancer Institute (NCI) | N=44 --> 0 | Trial completion date: Aug 2024 --> Nov 2023 | Suspended --> Withdrawn | Trial primary completion date: Aug 2024 --> Nov 2023

These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.

P2, N=107, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Mar 2024 --> Oct 2024

overall, tolerance was acceptable. The study did not meet the predetermined objective of PFS6 ≥ 35% and was stopped. A molecular characterization is ongoing to identify potential markers associated with prolonged stabilizations.

FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas.

Catequentinib in combination with metronomic temozolomide was well tolerated in this single patient. This patient’s response shows the promise of intentional, patient-specific care at the intersection of molecular testing and rational drug design. The patient will continue therapy and updated clinical and radiographic outcomes will be presented.

Genomic profiling revealed actionable targets and new therapeutic options for glioblastoma pts. A full and updated overview of patient characteristics, actionable targets and survival data will be presented at the meeting.

In HGG (glioblastoma, n=25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n=24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). No treatment-related deaths occurred.ConclusionsErda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.